Background: Muscarinic-receptor antagonists and β-adrenoceptor agonists are used, alone or in combination, as first-line treatment for chronic obstructive pulmonary disease. Both drugs decrease airway smooth muscle tone by post-junctional mechanisms but they may have opposing effects on pre-junctional acetylcholine (ACh)-release. Methods: We studied the effects of the muscarinic-receptor antagonist glycopyrronium (GLY), the β-adrenoceptor agonist indacaterol (IND) and their combination on electrically-induced ACh-release and contractile response in isolated bovine trachealis. Data were analyzed by paired t-test and analysis of variance for repeated or independent measures with Newmann-Keuls post-hoc test when appropriate. Results: GLY 10-8 M decreased contractile response by 19 ± 6% (p = 0.010) without altering ACh-release. GLY 10-7 M and 10-6 M almost abolished contractile responses even if the ACh-release was increased by 27 ± 19% (p < 0.001) and 20 ± 8% (p = 0.004), respectively. IND 10-7 M had no significant effects on contractile response and ACh-release, whereas IND 10-6 M reduced contractile response by 24 ± 12% (p = 0.002) without altering ACh-release. IND 10-5 M decreased contractile response by 51 ± 17% (p < 0.001) and ACh-release by 22 ± 11% (p = 0.004). Co-incubation with GLY 10-8 M and IND 10-7 M did not alter ACh-release but inhibited contractile response by 41 ± 8% (p < 0.001). The latter effect was greater than with GLY 10-8 M, or IND 10-7 M, or IND 10-6 M given separately (p < 0.001 for all). The increment of ACh-release caused by GLY was attenuated by IND 10-5 M, though this did not affect contractile response. Conclusions: At equimolar concentration, GLY alone attenuates airway smooth muscle contraction more than IND, despite an increased ACh-release. Combination of GLY with IND at submaximal concentrations has more than additive effect suggesting a synergistic post-junctional effect. Adding GLY to IND provides a greater inhibitory effect on airway smooth muscle contraction than increasing IND concentration.
Interactions between glycopyrronium and indacaterol on cholinergic neurotransmission and contractile response in bovine trachealis
Brusasco V.
2017-01-01
Abstract
Background: Muscarinic-receptor antagonists and β-adrenoceptor agonists are used, alone or in combination, as first-line treatment for chronic obstructive pulmonary disease. Both drugs decrease airway smooth muscle tone by post-junctional mechanisms but they may have opposing effects on pre-junctional acetylcholine (ACh)-release. Methods: We studied the effects of the muscarinic-receptor antagonist glycopyrronium (GLY), the β-adrenoceptor agonist indacaterol (IND) and their combination on electrically-induced ACh-release and contractile response in isolated bovine trachealis. Data were analyzed by paired t-test and analysis of variance for repeated or independent measures with Newmann-Keuls post-hoc test when appropriate. Results: GLY 10-8 M decreased contractile response by 19 ± 6% (p = 0.010) without altering ACh-release. GLY 10-7 M and 10-6 M almost abolished contractile responses even if the ACh-release was increased by 27 ± 19% (p < 0.001) and 20 ± 8% (p = 0.004), respectively. IND 10-7 M had no significant effects on contractile response and ACh-release, whereas IND 10-6 M reduced contractile response by 24 ± 12% (p = 0.002) without altering ACh-release. IND 10-5 M decreased contractile response by 51 ± 17% (p < 0.001) and ACh-release by 22 ± 11% (p = 0.004). Co-incubation with GLY 10-8 M and IND 10-7 M did not alter ACh-release but inhibited contractile response by 41 ± 8% (p < 0.001). The latter effect was greater than with GLY 10-8 M, or IND 10-7 M, or IND 10-6 M given separately (p < 0.001 for all). The increment of ACh-release caused by GLY was attenuated by IND 10-5 M, though this did not affect contractile response. Conclusions: At equimolar concentration, GLY alone attenuates airway smooth muscle contraction more than IND, despite an increased ACh-release. Combination of GLY with IND at submaximal concentrations has more than additive effect suggesting a synergistic post-junctional effect. Adding GLY to IND provides a greater inhibitory effect on airway smooth muscle contraction than increasing IND concentration.
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